All three guidelines are based on "evidence-based practice." The ideal is that each treatment recommendation is backed by a substantial body of scientific data, preferably rigorously conducted clinical trials and meta-analyses of these trials. The APA Guideline lists more than a thousand footnotes, most with more than one citation. A lot of evidence, but is it telling us what we need to know?

The guidelines cover a lot of ground, including non-meds treatments, and on all the main points they are in general accord. But let’s narrow our focus (for now) to antidepressants. In brief:

In general, over the short term, for moderate-to-severe depressions, there is strong evidence that antidepressants will improve your condition, even if only somewhat. For milder depressions, the evidence suggests giving antidepressants a miss.

The various classes of antidepressants are comparable in efficacy but not in side effects. Thus, side effects becomes the main clinical consideration in matching antidepressant to patient. This translates to new-generation antidepressants (such as SSRIs and SNRIs) being regarded as first-line treatments.

If your first antidepressant doesn’t work, there is strong evidence that it is worth trying a second antidepressant. The odds go way down when trying a third.

The evidence also indicates that if your antidepressant is working, it is a good idea to stay on it for a year.

But what the lack of evidence tells us may be far more revealing, namely:

Which Med Should You Try First?

We have no advance knowledge of which particular class or brand of antidepressant will work best to improve a patient’s individual condition. An "energizing" depressant for a "vegetative" depression, for instance, sounds like a good idea. Too bad there are no studies involving modern meds to test that proposition.

The APA Guideline, to its credit, did grapple with this very issue. But the only studies it had to go on were small ones that compared two ancient types of antidepressants, MAOIs to TCAs. Not very helpful.

NICE had different motives. Being a part of the UK’s public health system, they were looking for value for money. Accordingly, their Guideline recommended a generic SSRI as a first option for any patient presenting with severe depression. That may be good for the taxpayer, but is it good for the patient?

If this particular NICE recommendation sounds like an absurdity of socialized medicine, the same mentality also drives for-profit managed care in the US. Other than cost and potential side effects, we have no way of knowing where to start. You have the lack of a decent evidence base to thank for that.

If Your First Med Fails, What Next?

All three guidelines cite the NIMH-underwritten STAR*D real-world trials of the mid-2000s. Nearly 3,000 patients were started on the SSRI antidepressant, Celexa. The non-responders and partial responders were then switched to other options, including a different antidepressant, a combination of antidepressants, and so on. Enough patients improved to warrant each of these options, but - to the apparent surprise of the researchers - no one option delivered a better result than the others. Additional studies might have teased out which types of patients were likely to respond best to particular second and third options. Alas, no studies.

Verdict: Your doctor may call it practicing medicine. We know it as pill roulette.

If Meds Treatment Fails or Makes You Worse, Then What?

STARD was intended to test fourth and fifth and sixth options on patients, but they just about ran out of subjects after Round Three. Back in those days, the assumption was that if you kept trying long enough you were bound to come across something that made you better. STARD severely challenged that assumption. By Round Three, the odds for improvement (at least on antidepressants) dropped considerably. Sure, maybe fourth or fifth or sixth time lucky. But, with nothing to go on, don’t hold your breath waiting.

So, here you are, contemplating another round of pill roulette. Fortunately, there is a more sensible option, namely to revisit the diagnosis. The only reason you may be treatment-resistant is that you may have been taking meds for a condition you don’t have. You may have bipolar, instead. Credit the APA and CANMAT for pointing this out. You will still be playing pill roulette, but at least with meds that have a chance of working for you.

How Long Should You Stay On Your Antidepressant?

All three guidelines cite an array of clinical trials and meta-analyses of those trials in support of the proposition that staying on your antidepressant (provided it is working for you) for a good 12 months or so significantly reduces risk of relapse. But we have no studies that go beyond two years. Alas, there are legitimate concerns over the long-term effects of antidepressants. Is an antidepressant good or bad for you this far out? Once again, we are flying in the dark.

To conclude …

A short post cannot possibly do justice to all the nuances of treating depression. In future posts, we will look at the issues raised here (plus additional ones) in a lot more depth. In the meantime, I urge you to share your experiences with antidepressants (and related meds). As always, you are the true experts …

John is an author and advocate for Mental Health. He wrote for HealthCentral as a patient expert for Depression and Bipolar Disorder.